Repeated stimulation of the beta-adrenergic receptors of the rat pineal gland results in a loss of responsiveness of the cyclic adenosine 3',5'-monophosphate (cAMP) system of the gland. We determined if less cAMP accumulated in rat pineal in vivo after a second dose of 1-isoproterenol, and whether the changes observed could be explained as the consequences of decreased adenylate cyclase activity and/or increased low Km phosphodiesterase activity.